Tenofovir alafenamide (TAF), a new formulation that reaches higher levels in cells but allows for lower dosing, was as effective as the current tenofovir disoproxil fumarate (TDF) formulation but had less impact on markers of kidney function and bone turnover, researchers reported at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2013) this week in Denver.

Tenofovir (Viread, also in the Truvada, Atripla, Complera, and Stribild coformulations) is among the most widely used antiretroviral drugs, as it is highly effective and generally regarded as safe and well-tolerated. However, it can cause kidney toxicity in susceptible individuals and is associated with bone loss that begins soon after starting treatment. The long-term consequences of these side effects are a growing concern in light of guidelines recommending earlier treatment and expanding use of Truvada for pre-exposure prophylaxis (PrEP).

Gilead Sciences' new TAF formulation produces 5-fold higher concentrations of active tenofovir diphosphate in the cells that harbor HIV, but drug levels in the blood remain much lower compared with TDF. This enables reduced dosing that is expected to have less detrimental effects on the kidneys and bones.

Paul Sax from Brigham and Women's Hospital in Boston presented late-breaking results from a Phase 2 study (GS-US-292-0102) comparing TAF at 10 mg versus TDF at 300 mg, both as part of a single-tablet regimen that also includes the integrase inhibitor elvitegravir, cobicistat (a pharmacoenhancer or "booster"), and emtricitabine. The TDF-containing coformulation is marketed as Stribild; the TAF version is not yet approved. Given the apparent advantages of TAF, advocates have asked Gilead to request approval for the single agent as well as the new coformulation.

This double-blind, placebo-controlled trial included 170 previously untreated people with HIV who were randomly assigned (2:1) to receive the TAF or TDF coformulations once-daily for 48 weeks.

Almost all participants were men, more than two-thirds were white, nearly one-third were black, and the median age was about 35 years. The median baseline CD4 T-cell count was about 390 cells/mm3(though about 15% had less than 200 cells/mm3) and the median viral load was approximately 40,000 copies/mL. At study entry they had normal kidney function with a median estimated glomerular filtration rate (eGFR) of 115 mL/min. People with hepatitis B or C coinfection were excluded.

48-week data showed little change: 88.4% of people in the TAF arm and 87.9% in the TDF arm achieved undetectable viral load in an intent-to-treat "snapshot' analysis" (90.2% vs 89.7% in a missing=failure analysis).

Virological non-response was a bit less common in the TAF group (6.3%) than in the TDF group (10.3%); more Stribild recipients discontinued due to lack of efficacy (3.4% vs none), but more TAF recipients stopped early due to adverse events (3.6% vs none) or had missing 48-week data (5.4% vs 1.7%).

6 participants -- 3 in each arm -- who experienced virological failure underwent resistance testing, which indicated that no one in the TAF arm developed resistance but 2 people taking Stribild showed double resistance mutations (M184V/K70E and M184V/E92Q).

26 patients participated in a pharmacokinetic substudy, which showed:

o The TAF coformulation produced trough (minimum) and total (area under the curve) tenofovir plasma concentrations of 11 ng/mL and 326 ng*hr/mL, respectively, compared with 83 ng/mL and 3,795 ng*hr/mL with the TDF coformulation.

The TAF and TDF coformulations were both generally safe and well-tolerated, with most side-effects being mild or moderate.

Most adverse events occurred at similar rates in both groups, but nausea was nearly twice as common in the TAF arm (21% vs 12%).

There were no treatment-related serious adverse events in either arm.

Laboratory abnormalities were also generally comparable in the 2 treatment arms.

However, more people in the TAF arm had abnormally high low-density lipoprotein (LDL or "bad cholesterol"); Sax explained that tenofovir has a lipid-lowering effect in the blood, but this didn't happen to the same extent with TAF because its plasma concentration is so much lower.

Turning to kidney function, there was less change in eGFR over time in the TAF coformulation arm compared with the Stribild arm (-5.5 and -10.0, respectively).

No cases of renal tubulopathy were seen in either arm, and no one discontinued therapy due to kidney-related side effects.

Looking at bone loss, bone mineral density -- as measured by DEXA scans taken at 24 and 48 weeks -- decreased less in the TAF arm than in the TDF arm both at the spine (-1.00 vs -3.37) and at the hip (-0.62 vs -2.39).

One-third of participants taking the TAF coformulation experienced no change in hip bone density, compared with just 7% in the Stribild arm.

A related poster presentation showed that TAF did not lead to unexpectedly high concentrations of tenofovir in bone-forming cells known as primary osteoblasts and did not have a cytotoxic effect on these cells at clinically relevant concentrations in a laboratory study.

Treatment-naive patients taking the TAF coformulation had high levels of viral suppression over 48 weeks, comparable to those seen with Stribild, the researchers summarized. However, patients taking the TAF coformulation had a smaller decrease in eGFR and significantly smaller decreases in bone mineral density of the hip and spine.

Kidney biomarker changes have been attributed to cobicistat inhibiting renal tubule secretion, Sax noted. But it not clear why this effect is smaller with TAF than with TDF, since the dose of cobicistat in the coformulations is the same.

Sax added that Phase 3 studies are underway and researchers are making an "aggressive attempt" to enroll more women.